Implications of gene-behavior interactions: prevention and intervention for obesity.
ABSTRACT: A vast body of research exists to demonstrate that obesity is a complex disorder with a strong genetic basis and a multifactorial etiology. Yet despite the overwhelming evidence that genes play an important role in the development of obesity, many people argue that the increasing prevalence of obesity is simply due to an abundance of palatable food and a dearth of opportunities for physical exercise. While activity and eating behaviors contribute substantially to the development of obesity, considering these to be the only etiologic factors is directly contradictory to what is now known about how eating and energy balance are regulated. Our understanding of the molecular processes controlling eating behavior, in particular, has accelerated exponentially in the last 10 years, and this is one area in which obesity genetics has made great progress. Our challenge is to understand more fully how genetic variation may interact with behavioral factors to influence the regulation of body weight and adiposity. Although exercise and diet strategies are used routinely for obesity treatment, there is a huge variability in how individuals respond to these interventions. There is also a substantial amount of evidence that such responses may also be regulated by genes. Understanding gene-response relationships is the key to developing more efficacious intervention and prevention programs for obesity.
Project description:<h4>Objectives</h4>Increased availability of high-calorie palatable food in most countries has resulted in overconsumption of these foods, suggesting that excessive eating is driven by pleasure, rather than metabolic need. The behavior contributes to the rise in eating disorders, obesity, and associated pathologies like diabetes, cardiac disease, and cancers. The mesocorticolimbic dopamine and homeostatic circuits are interconnected and play a central role in palatable food intake. The endocannabinoid system is expressed in these circuits and represents a potent regulator of feeding, but the impact of an obesogenic diet on its expression is not fully known.<h4>Methods</h4>Food intake and body weight were recorded in male Wistar rats over a 6-week free-choice regimen of high fat and sugar; transcriptional regulations of the endocannabinoid system were examined post-mortem in brain reward regions (prefrontal cortex, nucleus accumbens, ventral tegmental area, and arcuate nucleus). K-means cluster analysis was used to classify animals based on individual sensitivity to obesity and palatable food intake. Endocannabinoid levels were quantified in the prefrontal cortex and nucleus accumbens. Gene expression in dopamine and homeostatic systems, including ghrelin and leptin receptors, and classical homeostatic peptides, were also investigated.<h4>Results</h4>The free-choice high-fat -and sugar diet induced hyperphagia and obesity in rats. Cluster analysis revealed that the propensity to develop obesity and excessive palatable food intake was differently associated with dopamine and endocannabinoid system gene expression in reward and homeostatic brain regions. CB2 receptor mRNA was increased in the nucleus accumbens of high sugar consumers, whereas CB1 receptor mRNA was decreased in obesity prone rats.<h4>Conclusions</h4>Transcriptional data are consistent with observations of altered dopamine function in rodents that have access to an obesogenic diet and point to cannabinoid receptors as GPCR targets involved in neuroplasticity mechanisms associated with maladaptive intake of palatable food.
Project description:The obesity epidemic is believed to be driven by a food environment that promotes consumption of inexpensive, convenient, high-calorie, palatable foods. Individual differences in obesity susceptibility or resistance to weight loss may arise because of alterations in the neurocircuitry supporting food reward and eating habits. In particular, dopamine signaling in the ventromedial striatum is thought to encode food reward and motivation, whereas dopamine in the dorsal and lateral striatum orchestrates the development of eating habits. We measured striatal dopamine D2-like receptor binding potential (D2BP) using positron emission tomography with [(18)F]fallypride in 43 human subjects with body mass indices (BMI) ranging from 18 to 45?kg?m(-)(2). Opportunistic eating behavior and BMI were both positively associated with D2BP in the dorsal and lateral striatum, whereas BMI was negatively associated with D2BP in the ventromedial striatum. These results suggest that obese people have alterations in dopamine neurocircuitry that may increase their susceptibility to opportunistic overeating while at the same time making food intake less rewarding, less goal directed and more habitual. Whether or not the observed neurocircuitry alterations pre-existed or occurred as a result of obesity development, they may perpetuate obesity given the omnipresence of palatable foods and their associated cues.
Project description:Emerging data indicate that adults with binge eating may exhibit an attentional bias toward highly palatable foods, which may promote obesogenic eating patterns and excess weight gain. However, it is unknown to what extent youth with loss of control (LOC) eating display a similar bias. We therefore studied 76 youth (14.5?±?2.3 years; 86.8% female; BMI-z 1.7?±?.73) with (n?=?47) and without (n?=?29) reported LOC eating. Following a breakfast to reduce hunger, youth participated in a computerized visual probe task of sustained attention that assessed reaction time to pairs of pictures consisting of high palatable foods, low palatable foods, and neutral household objects. Although sustained attentional bias did not differ by LOC eating presence and was unrelated to body weight, a two-way interaction between BMI-z and LOC eating was observed (p?=?.01), such that only among youth with LOC eating, attentional bias toward high palatable foods versus neutral objects was positively associated with BMI-z. These findings suggest that LOC eating and body weight interact in their association with attentional bias to highly palatable foods cues, and may partially explain the mixed literature linking attentional bias to food cues with excess body weight.
Project description:Use of nonnutritive sweeteners (NNSs), which provide sweet taste with few to no calories, has increased, but data on whether children's hedonic responses to NNSs differ from nutritive sugars or from adults' hedonic responses are limited.Most preferred levels of sucrose and the NNS sucralose were determined via a forced-choice tracking procedure in 48 children, 7-14 years (mean?=?10 years), and 34 adults. Each participant also rated the liking of these taste stimuli, as well as varying concentrations of aspartame on 3- and 5-point facial hedonic scales. Anthropometric measures were obtained, and motives for palatable food intake were assessed with the Palatable Eating Motives Scale (PEMS, adults) and Kids PEMS.While use of the 3-point scale showed no age-related differences in liking of sweeteners, the 5-point scale showed that more children than adults liked higher concentrations of sucrose, sucralose, and aspartame, and the tracking procedure showed that children most preferred higher concentrations of sucrose and sucralose than adults. Regardless of age, sweet preference did not differ between obese and nonobese participants and showed no association with motives for eating palatable foods. Children's body mass index z-scores were positively associated with social and conformity motive scores for eating palatable foods.Research should move beyond measures of variation in sweet taste hedonics to include identifying motives, and the physiological and psychological consequences of eating sweets, to shed light on what children are more vulnerable to develop unfavorable eating habits, increasing risk for obesity, and other diseases.
Project description:Obesity is an important health problem with a strong environmental component that is acquiring pandemic proportion. The high availability of caloric dense foods promotes overeating potentially causing obesity. Animal models are key to validate novel therapeutic strategies, but researchers must carefully select the appropriate model to draw the right conclusions. Obesity is defined by an increased body mass index greater than 30 and characterized by an excess of adipose tissue. However, the regulation of food intake involves a close interrelationship between homeostatic and non-homeostatic factors. Studies in animal models have shown that intermittent access to sweetened or calorie-dense foods induces changes in feeding behavior. However, these studies are focused mainly on the final outcome (obesity) rather than on the primary dysfunction underlying the overeating of palatable foods. We describe a protocol to study overeating in mice using diet-induced obesity (DIO). This method can be applied to free choice between palatable food and a standard rodent chow or to forced intake of calorie-dense and/or palatable diets. Exposure to such diets is sufficient to promote changes in meal pattern that we register and analyze during the period of weight gain allowing the longitudinal characterization of feeding behavior in mice. Abnormal eating behaviors such as binge eating or snacking, behavioral alterations commonly observed in obese humans, can be detected using our protocol. In the free-choice procedure, mice develop a preference for the rewarding palatable food showing the reinforcing effect of this diet. Compulsive components of feeding are reflected by maintenance of feeding despite an adverse bitter taste caused by adulteration with quinine and by the negligence of standard chow when access to palatable food is ceased or temporally limited. Our strategy also enables to identify compulsive overeating in mice under a high-caloric regime by using limited food access and finally, we propose complementary behavioral tests to confirm the non-homeostatic food-taking triggered by these foods. Finally, we describe how to computationally explore large longitudinal behavioral datasets.
Project description:BACKGROUND:Certain eating behaviors are common among women with obesity. Whether these behaviors influence outcomes in weight loss programs, and whether such programs affect eating behaviors, is unclear. METHODS:Our aim was to examine the effect of baseline eating behaviors on intervention adherence and weight among postmenopausal women with overweight or obesity, and to assess intervention effects on eating behaviors. Four hundred and 39 women (BMI ?25?kg/m2) were randomized to 12?months of: i) dietary weight loss with a 10% weight loss goal ('diet'; n?=?118); ii) moderate-to-vigorous intensity aerobic exercise for 225 mins/week ('exercise'; n?=?117); iii) combined dietary weight loss and exercise ('diet + exercise'; n?=?117); or iv) no-lifestyle change control (n?=?87). At baseline and 12?months, restrained eating, uncontrolled eating, emotional eating and binge eating were measured by questionnaire; weight and body composition were assessed. The mean change in eating behavior scores and weight between baseline and 12?months in the diet, exercise, and diet + exercise arms were each compared to controls using the generalized estimating equation (GEE) modification of linear regression adjusted for age, baseline BMI, and race/ethnicity. RESULTS:Baseline restrained eating was positively associated with change in total calories and calories from fat during the dietary intervention but not with other measures of adherence. Higher baseline restrained eating was associated with greater 12-month reductions in weight, waist circumference, body fat and lean mass. Women randomized to dietary intervention had significant reductions in binge eating (-?23.7%, p?=?0.005 vs. control), uncontrolled eating (-?24.3%, p?<?0.001 vs. control), and emotional eating (-?31.7%, p?<?0.001 vs. control) scores, and a significant increase in restrained eating (+?60.6%, p?<?0.001 vs. control); women randomized to diet + exercise reported less uncontrolled eating (-?26.0%, p?<?0.001 vs. control) and emotional eating (-?22.0%, p?=?0.004 vs. control), and increased restrained eating (+?41.4%, p?<?0.001 vs. control). Women randomized to exercise alone had no significant change in eating behavior scores compared to controls. CONCLUSIONS:A dietary weight loss intervention helped women modify eating behaviors. Future research should investigate optimal behavioral weight loss interventions for women with both disordered eating and obesity. TRIAL REGISTRATION:NCT00470119 (https://clinicaltrials.gov). Retrospectively registered May 7, 2007.
Project description:Compulsive, binge eating of highly palatable food constitutes a core feature of some forms of obesity and eating disorders, as well as of the recently proposed disorder of food addiction. Trace amine-associated receptor 1 (TAAR1) is a highly conserved G-protein-coupled receptor bound by endogenous trace amines. TAAR1 agonists have been shown to reduce multiple behavioral effects of drugs of abuse through their actions on the mesocorticolimbic system. In this study, we hypothesized that TAAR1 may have a role in compulsive, binge-like eating; we tested this hypothesis by assessing the effects of a TAAR1 agonist, RO5256390, in multiple excessive feeding-related behaviors induced by limiting access to a highly palatable diet in rats. Our results show that RO5256390 blocked binge-like eating in rats responding 1?h per day for a highly palatable sugary diet. Consistent with a palatability-selective effect, drug treatment selectively reduced the rate and regularity of palatable food responding, but it did not affect either baseline intake or food restriction-induced overeating of the standard chow diet. Furthermore, RO5256390 fully blocked compulsive-like eating when the palatable diet was offered in an aversive compartment of a light/dark conflict box, and blocked the conditioned rewarding properties of palatable food, as well as palatable food-seeking behavior in a second-order schedule of reinforcement. Drug treatment had no effect on either anxiety-like or depressive-like behavior, and it did not affect control performance in any of the tests. Importantly, rats exposed to palatable food showed decreased TAAR1 levels in the medial prefrontal cortex (mPFC), and RO5256390 microinfused into the infralimbic, but not prelimbic, subregion of the mPFC-reduced binge-like eating. Altogether, these results provide evidence for TAAR1 agonism as a novel pharmacological treatment for compulsive, binge eating.
Project description:The anti-obesity medication rimonabant, an antagonist of cannabinoid type-1 (CB(1)) receptor, was withdrawn from the market because of adverse psychiatric side effects, including a negative affective state. We investigated whether rimonabant precipitates a negative emotional state in rats withdrawn from palatable food cycling. The effects of systemic administration of rimonabant on anxiety-like behavior, food intake, body weight, and adrenocortical activation were assessed in female rats during withdrawal from chronic palatable diet cycling. The levels of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), and the CB(1) receptor mRNA and the protein in the central nucleus of the amygdala (CeA) were also investigated. Finally, the effects of microinfusion of rimonabant in the CeA on anxiety-like behavior, and food intake were assessed. Systemic administration of rimonabant precipitated anxiety-like behavior and anorexia of the regular chow diet in rats withdrawn from palatable diet cycling, independently from the degree of adrenocortical activation. These behavioral observations were accompanied by increased 2-AG, CB(1) receptor mRNA, and protein levels selectively in the CeA. Finally, rimonabant, microinfused directly into the CeA, precipitated anxiety-like behavior and anorexia. Our data show that (i) the 2-AG-CB(1) receptor system within the CeA is recruited during abstinence from palatable diet cycling as a compensatory mechanism to dampen anxiety, and (ii) rimonabant precipitates a negative emotional state by blocking the beneficial heightened 2-AG-CB(1) receptor signaling in this brain area. These findings help elucidate the link between compulsive eating and anxiety, and it will be valuable to develop better pharmacological treatments for eating disorders and obesity.
Project description:BACKGROUND:Little is known about how mothers respond to their child eating palatable foods. OBJECTIVES:The objectives of the study are to examine maternal behaviours when children are presented with a large portion of energy-dense palatable food in an experimental setting and to examine differences by child weight status. METHODS:Mother-child dyads (N = 37) (mean child age 70.8 months) participated in a videotaped eating protocol with cupcakes. Anthropometrics were measured. Videos were analysed using discourse analysis and were reliably coded for the presence or absence of the most salient theme. Analysis of variance examined theme presence by child and mother weight status. RESULTS:Mothers disavowed responsibility for their child's eating. Mothers were observed to roll their eyes at the child, throw their hands up in exasperation and distance themselves both physically and emotionally when the child ate the cupcakes voraciously or with high enjoyment. Mothers of children with obesity (vs recommended weight) engaged in more counts of disavowal (p = 0.01). CONCLUSIONS:Mothers of children with obesity distanced themselves from their child, seeming to disavow responsibility for the child's eating of 'junk food'. Mothers may respond to their child's seemingly gluttonous eating by disavowing responsibility due to the stigma of being a parent of a child with obesity.
Project description:Endogenous cannabinoid signaling, mediated predominately by CB1 receptor activation, is involved in food intake control and body weight regulation. Despite advances in determining the role of the CB1 receptor in obesity, its involvement in the driven nature of eating pathologies has received little attention. The present study examined CB1 receptor alterations as a consequence of dietary-induced binge eating in female Sprague Dawley rats. Four control groups were used to control for calorie restriction and highly palatable food variables characterizing this behavioral model. All groups were kept on their respective feeding schedules for 6-weeks and were given a uniform 33% calorie restriction (~22 h food deprivation) prior to sacrifice. Our findings indicate that regional CB1 mRNA and density were influenced by dietary conditions, but were not specific to the dietary-induced binge eating paradigm used. An increase of approximately 50% (compared with naive controls) in CB1 receptor mRNA levels in the nucleus of the solitary tract as measured by in situ hybridization was found in animals receiving continuous access to a highly palatable food (i.e., vegetable shortening with 10% sucrose). This group also had a significant increase in body weight and adiposity. An approximate 20% reduction in CB1 mRNA was observed in the cingulate cortex (areas 1 and 2) in animals exposed to an intermittent schedule of feeding, compared with groups that had ad libitum feeding schedules (i.e., continuous access and naive controls). Receptor density as measured by [(3)H]CP55,940 autoradiography, was reduced by approximately 30% in the nucleus accumbens shell region in groups receiving repeated access to the highly palatable food. Taken together, these findings indicate that dietary conditions can differentially influence CB1 receptors in forebrain and hindbrain regions.